Worldwide, prostate cancer is the third most common cancer and the cause of 6% of cancer deaths in men (M. D. Parkin et al., Eur. J. Cancer, 2001, 37: S4-S66). Its incidence and mortality vary in different parts of the world and are highest in the Western countries (J. M. Chan et al., J. Urol., 2004, 172: S13-S16; K. D. Linton et al., Cancer Treat. Rev., 2003, 29: 151-160). In the U.S., prostate cancer is the most frequently diagnosed and the second leading cause of cancer death in men (A. Jemal et al., Cancer J. Clin., 2003, 53: 5-26). However, despite these high death rates, more men die with prostate cancer than from the disease (J. E. Johansson et al., JAMA, 1997, 277: 467; P. C. Alberstein et al., JAMA, 1998, 280: 975). Since the dilemma in managing patients with prostate cancer is that only a fraction of cases lead to cancer-related death, there is a great need to accurately assess the risk of disease progression in patients with prostate cancer so that appropriate treatment options can be considered.
Several clinical parameters including tumor stage, tumor grade as measured by the Gleason score, and the serum level of prostate-specific antigen (PSA) are typically used to assess the risk of disease progression at the time of diagnosis (A. W. Partin et al., JAMA, 1997, 277: 1445-1451). However, with the adoption of population-based PSA screening, the majority of men in the U.S., who are diagnosed with prostate cancer, are considered at low to intermediate risk for disease-specific mortality while they will often die of co-morbidities. A recent study (R. Etzioni et al., J. Natl. Cancer Inst., 2002, 94: 981-990) has demonstrated that PSA screening may in fact lead to the over-diagnosis and over-treatment of patients with prostate cancer, suggesting that some patients who undergo radical prostatectomy might have lived out their lives without any symptoms of the disease.
Important clinical trials have begun to evaluate watchful-waiting protocols, in which the decision to have surgery is postponed until disease progression is observed, because the risk of waiting as opposed to having immediate surgery is not fully known at the time of initial diagnosis (R. Choo et al., J. Urol., 2002, 167: 1664-1669). One important limitation to current watchful-waiting protocols lies in the subjective criteria used to select patients. If the likelihood of disease progression could be more accurately predicted at diagnosis, the success of such protocols would improve, allowing more men to remain on watchful-waiting protocols for clinically localized disease.
Although surgery may be unnecessary for some patients with clinically localized disease, others will require more aggressive treatment despite having localized disease. After radical prostatectomy, the disease recurs in an estimated 15-30% of patients, suggesting that undetected disease may have spread beyond the prostate gland before surgery (M. Han et al., Urol. Clin. North Am., 2001, 29: 555-565; S. G. Roberts et al., Mayo Clin. Proc., 2001, 76: 576-581). Monograms have been developed that use pretreatment clinical and pathologic parameters to evaluate the likelihood of disease-free survival after radical prostatectomy (M. W. Kattan et al., J. Natl. Cancer Inst., 1998, 90: 766-771) or brachytherapy (M. W. Kattan et al., Urol., 2001, 58: 393-399) for localized prostate cancer. However, these and other models have limitations as demonstrated by good but not excellent associations with outcome (P. L. Ross et al., J. Urol., 2001, 165: 1562-1568).
Given the limitations of current monograms to accurately predict which patients have the greatest risk of developing aggressive prostate cancer, researchers have been focusing on identifying and characterizing biomarkers for prostate diseases. Attempts to explore genetic correlates of tumor behavior have revealed alterations in a number of candidate genes associated with prostate cancer progression, including, for example, loss of p53, amplification of myc, loss of p27, and loss of PTEN. However, no single gene has been shown to have sufficient prognostic utility to warrant clinical implementation.
Recently, genomic methodologies have been used to discover consistent gene expression patterns associated with a given histological or clinical phenotype (T. R. Golub et al., Science, 1999, 286: 531-537; C. M Perou et al., Nature, 2000, 406: 747-752; and L. J. van't Veer et al., Nature, 2002, 415: 530-536). Complementary DNA (cDNA) microarrays have allowed characterization of gene expression profiles for prostate cancer tissue, benign prostate disease tissue, and normal prostate tissue (J. Luo et al., Cancer Res., 2001, 61: 483-4688; J. A. Magee et al., Cancer Res., 2001, 61: 5692-5696; S. M. Dhanasekaran et al., Nature, 2001, 412: 822-826; D. Singh et al., Cancer Cell, 2002, 1: 203-209; J. B. Welsh et al., Cancer Res., 2001, 61: 5974-5978; J. H. Luo et al., Mol. Carcinog., 2002, 33: 25-35).
Although these and other studies have led to the identification of discrete molecular signatures, the development of a robust signature to characterize aggressive prostate cancer has yet to be achieved. There clearly remains a need for improved methods for diagnosing and classifying prostate cancer diseases, and for predicting prostate cancer progression. In particular, systems that would allow physicians to determine which patients might benefit from a more aggressive treatment, and which patients might be spared unnecessary and potentially harmful interventions are highly desirable.